Effects of diabetes and hypertension on glomerular transforming growth factor-beta receptor expression.

Background: Several studies have suggested that transforming growth factor-beta1 (TGF-beta1) is an important determinant of diabetic glomerular injury. TGF-beta1 forms a heteromeric complex with two cellular receptor subtypes, designated TGF-beta RII and TGF-beta RI, but the effects of diabetes mellitus on glomerular TGF-beta receptor expression have not been completely elucidated. We first compared the effect of experimental type I diabetes mellitus and uninephrectomy on glomerular TGF-beta receptor expression in spontaneously hypertensive rats (SHRs), and then sought to determine whether changes in TGF-beta receptor expression were strain specific by studying normotensive Wistar-Kyoto (WKY) rats.
Methods: Five groups of male SHRs were studied. The first group received streptozotocin (60 mg/kg IV) and was studied after one week. The second group received streptozotocin and was studied after two weeks. The third group received streptozotocin (60 mg/kg IV) but received insulin to maintain euglycemia. The fourth group of age-matched SHRs served as the control group, while a fifth group of SHRs underwent uninephrectomy. Four groups of male WKY rats were also studied. The first group of WKY rats served as the age-matched control group. The second group of WKY rats received streptozotocin, while a third group of WKY rats underwent uninephrectomy. The fourth group underwent uninephrectomy and received streptozotocin. At each time point, glomeruli were isolated for protein extraction, and the protein was subjected to Western blot analysis of TGF-beta RII and TGF-beta RI expression.
Results: Basal expression of both TGF-beta receptors per microgram of glomerular protein was similar in normotensive WKY rats and hypertensive SHRs. Hyperglycemia (blood glucose level, 17.8 +/- 2.9 mmol/L) led to an early twofold increase in TGF-beta RII protein expression and a fourfold increase in TGF-beta RI protein expression in the glomeruli of hypertensive diabetic SHRs compared with euglycemic SHRs (blood glucose level, 5.8 +/- 0.8 mmol/L), which was sustained after two weeks. Insulin treatment (blood glucose level, 5. 2 +/- 0.9 mmol/L) normalized both TGF-beta RII and TGF-beta RI expression in the glomeruli of SHRs that received streptozotocin. Glomerular capillary hypertension in the uninephrectomized SHRs led to a twofold increase in glomerular TGF-beta RII protein expression, but did not reproduce the effect of diabetes mellitus on TGF-beta RI expression. In contrast to the findings in SHRs, neither hyperglycemia (blood glucose level, 15.5 +/- 2.1 mmol/L), uninephrectomy, nor hyperglycemia (blood glucose level, 16.8 +/- 3.0 mmol/L) and uninephrectomy altered TGF-beta receptor expression in the glomeruli of normotensive WKY rats.
Conclusion: These studies support the hypothesis that hemodynamic factors and metabolic factors influence glomerular TGF-beta receptor in vivo in the SHRs.